Nesprin-1 mutations in human and murine cardiomyopathy

Abstract Mutations in LMNA , the gene encoding the nuclear membrane proteins, lamins A and C, produce cardiac and muscle disease. In the heart, these autosomal dominant LMNA mutations lead to cardiomyopathy frequently associated with cardiac conduction system disease. Herein, we describe a patient w...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2010-04, Vol.48 (4), p.600-608
Main Authors: Puckelwartz, Megan J, Kessler, Eric J, Kim, Gene, DeWitt, Megan M, Zhang, Yuan, Earley, Judy U, Depreux, Frederic F.S, Holaska, James, Mewborn, Stephanie K, Pytel, Peter, McNally, Elizabeth M
Format: Article
Language:English
Subjects:
Animals
Cardiomyopathies - genetics
Cardiomyopathies - metabolism
Cardiomyopathy
Cardiovascular
Cell Nucleus - metabolism
Echocardiography - methods
Fibroblasts - metabolism
Heterochromatin - metabolism
Humans
Lamin A/C
Laminin - genetics
Mice
Mutation
Mutation, Missense
Myocytes, Cardiac - cytology
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - physiology
Nesprin
Nuclear Envelope - metabolism
Nuclear membrane
Nuclear Proteins - genetics
Nuclear Proteins - physiology
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Summary:Abstract Mutations in LMNA , the gene encoding the nuclear membrane proteins, lamins A and C, produce cardiac and muscle disease. In the heart, these autosomal dominant LMNA mutations lead to cardiomyopathy frequently associated with cardiac conduction system disease. Herein, we describe a patient with the R374H missense variant in nesprin-1α, a protein that binds lamin A/C. This individual developed dilated cardiomyopathy requiring cardiac transplantation. Fibroblasts from this individual had increased expression of nesprin-1α and lamins A and C, indicating changes in the nuclear membrane complex. We characterized mice lacking the carboxy-terminus of nesprin-1 since this model expresses nesprin-1 without its carboxy-terminal KASH domain. These Δ/ΔKASH mice have a normally assembled but dysfunctional nuclear membrane complex and provide a model for nesprin-1 mutations. We found that Δ/ΔKASH mice develop cardiomyopathy with associated cardiac conduction system disease. Older mutant animals were found to have elongated P wave duration, elevated atrial and ventricular effective refractory periods indicating conduction defects in the myocardium, and reduced fractional shortening. Cardiomyocyte nuclei were found to be elongated with reduced heterochromatin in the Δ/ΔKASH hearts. These findings mirror what has been described from lamin A/C gene mutations and reinforce the importance of an intact nuclear membrane complex for a normally functioning heart.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2009.11.006